Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review)

Abstract

Lipoprotein‑associated phospholipase A2 (Lp‑PLA2), an important member of the phospholipase A2 superfamily, was originally investigated for its proinflammatory role in cardiovascular diseases. Recent studies have revealed its significant role in tumorigenesis: It can act as either a tumor promoter or a tumor suppressor depending on the context. The present review systematically outlined the dual mechanisms by which Lp‑PLA2 contributes to cancer pathogenesis. As a tumor promoter, it promotes cancer progression via the induction of epithelial‑mesenchymal transition, glutathione peroxidase 4‑mediated resistance to ferroptosis, and vascular endothelial growth factor‑-dependent angiogenesis; conversely, as a tumor suppressor, it inhibits tumor growth by suppressing the Wnt/β‑catenin pathway in breast cancer gene 1‑mutated cancers or by promoting apoptosis. Mechanistic investigations clarify the interactions between Lp‑PLA2 and critical oncogenic pathways, such as the Notch and HIF1α pathways, while emphasizing the functional dichotomy that is influenced by the microenvironment. Current evidence supports the development of microenvironment‑guided targeting strategies and the potential value of Lp‑PLA2 as a prognostic biomarker and therapeutic target. These findings contribute to a theoretical framework for comprehending the context‑dependent roles of Lp‑PLA2 and may guide the development of innovative therapeutic approaches.

Keywords: biomarker; cancer; ferroptosis; lipoprotein‑associated phospholipase a2; molecular mechanism; therapeutic target; tumor microenvironment.

Figure 1

A brief illustration of the catalytic active site of Lp-PLA2 and its catalytic mechanism. PLs typically feature a saturated fatty acid at the sn-1 position of glycerol, while the fatty acid at the sn-2 position may vary, being either saturated, monounsaturated, or polyunsaturated. Notably, polyunsaturated fatty acids at the sn-2 position are susceptible to oxidation under conditions of oxidative stress, leading to the formation of ox-PLs through a process referred to as lipid peroxidation. Lp-PLA2 is a hydrolase enzyme characterized by a catalytic triad active site (Ser273-Asp356-His376) that effectively catalyzes the hydrolysis of the oxidized fatty acid at the sn-2 position, resulting in the release of ox-FFAs and lyso-PLs (5). Lp-PLA2, lipoprotein-associated phospholipase a2; PLs, Phospholipids, ox-PLs, oxidized phospholipids, ox-FFAs, oxidized free fatty acids, lyso-PLs, lysophospholipids.

Figure 2

Opposing roles of Lp-PLA2 in different cancers: promoting or suppressing tumour progression. The circular diagram presented illustrates the diverse roles of Lp-PLA2, which is encoded by the PLA2G7 gene, in the process of carcinogenesis. The diagram is segmented into various colored sections that represent the oncogenic (red), anticarcinogenic (black), and regulatory (indicated by arrows) functions of Lp-PLA2. Each section provides detailed information regarding specific cancer types, relevant cell lines (such as THP-1 for PMA-differentiated macrophages and C666-1 for nasopharyngeal carcinoma), as well as the molecular mechanisms or alterations in gene expression that are modulated by Lp-PLA2. For example, in the context of breast cancer, Lp-PLA2 influences tumorigenesis by affecting the mutation status of BRCA1, whereas in hepatocellular carcinoma, it plays a role in the regulation of STAT3/STAT1 signaling pathways. Additionally, the diagram indicates variations in Lp-PLA2 expression levels (with upward arrows denoting increases and downward arrows indicating decreases) and outcomes from co-culture experiments (denoted by a plus sign). This visualization emphasizes the intricate interactions of Lp-PLA2 within tumour biology, highlighting its functional plasticity that is dependent on the specific context of various TMEs. AKT, protein kinase B; ALDH1A1, aldehyde dehydrogenase 1 family member A1; BRCA1, breast cancer gene 1; CD8, cluster of differentiation 8; ERK1/2, extracellular signal-regulated kinases 1 and 2; GPX4, glutathione peroxidase 4; HDAC3, histone deacetylase 3; HIF-1α, hypoxia-inducible factor-1 alpha; ICAM-1, intercellular adhesion molecule-1; IL-1β, interleukin-1 beta; IL-6, interleukin-6; JAK, Janus kinase; LPC, lysophosphatidylcholine; LP, lysophospholipid/lipid peroxidation; Lp-PLA2, lipoprotein-associated phospholipase a2; .MCP-1, monocyte chemoattractant protein-1; MMP-9, matrix metalloproteinase-9; mTORC1, mechanistic target of rapamycin complex 1; oxFFA, oxidized free fatty acid; PAF, platelet-activating factor; PAF-AH, platelet-activating factor acetylhydrolase; PI3K, phosphoinositide 3-kinase; PLA2G7, phospholipase A2 group VII; PGE2, prostaglandin E2; STAT, signal transducer and activator of transcription; THP-1, human monocytic leukemia cell line; TNF-α, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor; Wnt/β-catenin, wingless-type MMTV integration site family/β-catenin signaling pathway.

Figure 3

The role of Lp-PLA2 in lipid metabolic reprogramming and the associated downstream signaling pathways in cancer. Lp-PLA2 is notably upregulated in cancer. Its enzymatic product, LPC, serves dual oncogenic roles: i) Facilitating the assembly of lipid rafts to improve membrane fluidity and (ii) activating Gαi-ERK1/2 signaling through the LPC-GPCR pathway. Additionally, metabolites of AA derived from Lp-PLA2 contribute to tumor progression through two interrelated pathways: the established COX-2/PGE2 signaling cascade and the recently discovered 12-HETE-PPARγ pathway. Collectively, these mechanisms play a significant role in driving cancer pathogenesis. AA, arachidonic acid; ACC, acetyl-CoA carboxylase; AKT, protein kinase B; cAMP, cyclic adenosine monophosphate; CDK4, cyclin-dependent kinase 4; COX-2, cyclooxygenase-2; EP2, prostaglandin E2 receptor 2; ERK1/2, extracellular signal-regulated kinases 1 and 2; FASN, fatty acid synthase; GBY, G-protein βγ subunit; Gai, inhibitory G-protein α subunit; GPCR, G-protein-coupled receptor; 12-HETE-PPARγ, 12-hydroxyeicosatetraenoic acid-peroxisome proliferator-activated receptor γ; 12-LOX, 12-lipoxygenase; LPC, lysophosphati-dylcholine; Lp-PLA2, lipoprotein-associated phospholipase a2; mTOR, Mechanistic target of rapamycin; PC, phosphatidylcholine; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol-trisphosphate; PKA, protein kinase A; PPARγ, peroxisome proliferator-activated receptor γ; PGE2, prostaglandin E2; PTGER2, prostaglandin E2 receptor 2; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog family member A; VEGF, vascular endothelial growth factor.

Figure 4

Lp-PLA2-Driven immunosuppression in the TME. PLA2G7 orchestrates tumor immune evasion through two integrated mechanisms: (i) cell-intrinsic suppression of T lymphocyte proliferation to cripple antitumor immunity, and (ii) cell-extrinsic polarization of macrophages toward the M2 phenotype that establishes an immunosuppressive niche. These coordinated actions culminate in adverse clinical outcomes and acquired immunotherapy resistance. CD8, cluster of differentiation 8; CXCL9, C-X-C motif chemokine ligand 9; CXCL10, C-X-C motif chemokine ligand 10; HNF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL-10, interleukin-10; Lp-PLA2, lipoprotein-associated phospholipase a2; PD-L1, programmed death-ligand 1; PLA2G7, phospholipase A2 group VII; STAT1, signal transducer and activator of transcription 1; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor β; TME, tumor microenvironment.

Figure 5

Therapeutic strategies targeting Lp-PLA2 in tumor treatment. (A) Therapeutic strategies aimed at targeting Lp-PLA2 in the context of tumour treatment. Three distinct methodologies are presented: i) The small-molecule inhibitor darapladib, which enhances lipid metabolism, thereby increasing the susceptibility of cancer cells to ferroptosis. ii) Monoclonal antibodies (1H8 IgG and 1Ag VH-Fc) that selectively bind to specific epitopes of Lp-PLA2, effectively inhibiting the proliferation and migration of tumor cells. B and C the synergistic antitumor effects observed when darapladib is combined with PD-1 blockade. In vitro and in vivo studies both indicate that the combination of darapladib with a PD-1 inhibitor results in a significant reduction in tumor growth compared to the effects of monotherapy. AA, arachidonic acid; CCL5, C-C motif chemokine ligand 5; CD8, cluster of differentiation 8; CXCL10, C-X-C motif chemokine ligand 10; FFA, free fatty acid; IL-1β, interleukin-1 β; LPC, lysophosphatidylcholine; Lp-PLA2, lipoprotein-associated phospholipase a2; Lyso-PE, lysophosphatidylethanolamine; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; Ox-PE, oxidized phosphatidylethanolamine; PD-1, programmed cell death protein 1; PEP, phosphatidylethanolamine plasmalogen; PI3K-AKT, phosphoinositide 3-kinase-protein kinase B pathway; TAMs, tumour-associated macrophages; TNF-α, tumor necrosis factor-α.